This application relates to the use of ansamycin antibiotics as targeted therapeutic agents for the destruction of selected proteins and to novel compositions suited for this use. Destruction of selected proteins in accordance with the invention can be used in the treatment of cancer.
Targeted delivery of therapeutic agents as a means for treating cancer has been proposed by many authors. Conceptually, the idea is to deliver a toxic substance selectively to the cancer cells, thus reducing the general toxicity to the patient. This is theoretically possible, since many cancer cell types have been found to have increased levels of hormone receptors and similar receptors. For example, breast cancer cells may have elevated levels of HER2 receptors or estrogen receptors which result in hormone-stimulated growth of cancer cells, while androgen receptors are required for growth of many prostate cancers and mutation of the androgen receptors frequently occurs in advanced prostate cancer.
Hormone receptors have been used in studies on the feasibility of using direct targeted chemotherapy agents to certain classes of cells. Thus, for example, Lam et al., Cancer Treatment Reports 71: 901-906 (1987) have reported on estrogen-nitrosourea conjugates as potential cytotoxic agents against human breast cancer, while Brix et al., J. Cancer Res. 116: 538-539 (1990) have reported on studies of the use of androgen-linked alkylating agents as antineoplastic agents. See also, Eisenbrand et al., Acta Oncologica 28: 203-211 (1989). Myers and Villemez, Biochem. Biophys. Res. Commun. 163: 161-164 (1989) have disclosed the possibility of utilizing luteinizing hormone coupled to a truncated diphtheria toxin.
Benzoquinoid ansamycin antibiotics such as geldanamycin and herbimycin A are known to induce the destruction of certain protein tyrosine kinases including HER-2 receptors, insulin and insulin-like growth factor receptors and members of the src-family and rafkinase. In addition, benzoquinoid antibiotics can induce the selective degradation in vivo of receptors, including estrogen, androgen and progesterone receptors.
We have now found that compounds having an ansamycin antibiotic coupled to a targeting moiety which binds specifically to a protein, receptor or marker can provide effective targeted delivery of the ansamycin antibiotic leading to the degradation of proteins and death of the targeted cells. These compositions may have different specificity than the ansamycin alone, allowing for a more specific targeting of the therapy, and can be effective in instances where the ansamycin alone has no effect. Thus, the present invention provides an entirely new class of targeted chemotherapy agents with application, depending on the nature of the targeting moiety, to treatment of a variety of different forms of cancer. Such agents can further be used to promote selective degradation of proteins associated with the pathogenesis of others diseases, including antigens associated with autoimmune disorders and pathogenic proteins associated with Alzheimer""s disease.
Compounds in accordance with the invention comprise a targeting moiety which specifically binds to a target protein or cell population, and an ansamycin antibiotic, preferably separated by a spacer. Exemplary targeting moieties which may be employed in compounds of the invention include testosterone, estradiol, and tamoxifen. Preferred ansamycin antibiotics are geldanamycin and herbimycin A.